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Mucopolysaccharidosis (MPS) is a group of rare, inherited lysosomal storage disorders that affect glycosaminoglycan (GAG) degradation by the mutation in a lysosomal enzyme essential to GAG breakdown. The mutation can lead to the absence of the enzyme or a mutated inactive enzyme. Glycosaminoglycans are polysaccharides that play important roles in many tissues such as lubricant in joint fluid and the ground substance or bone and cartilage. MPS is clinically characterized by abnormalities in multiple organ systems and reduced life expectancy. There are several types of MPS.

Type	Disorder Name(s)	GAG Storage Material	Deficient Enzyme	Replacement Drug
MPS I	Hurler, Hurler-Scheie, Scheie	Dermatan sulfate, Heparan sulfate	Alpha-L-iduronidase	Laronidase (Aldurazyme®)
MPS II	Hunter	Dermatan sulfate, Heparan sulfate	Iduronate-2-sulfatase	Idursulfase (Elaprase®)
MPS III A-D	Sanfilippo	Heparan sulfate	Heparan-N-sulfatase alpha-N-acetylglucosaminidase acetyl-CoA; alpha-glucosaminide acetyltransferase N-acetylglucosamine 6-sulfatase
MPS IV A, B	Morquio	Keratan sulfate, chondroitin sulfate, keratan sulfate	Galactose-6-sulfatase Beta-galactosidase	A-Elosulfase alfa (Vimizim®)
MPS V	This is now known as Scheie Syndrome, a subtype of MPS I.
MPS VI	Maroteaux-Lamy	Dermatan sulfate, chondroitin sulfate	Arylsulfatase B	Galsulfase (Naglazyme®)
MPS VII	Sly syndrome	Dermatan sulfate, heparan sulfate, chondroitin sulfate	Beta-glucuronidase	Vestronidase alfa-vjbk (Mepsevii™)
MPS IX		Hyaluronan	Hyaluronidase

The failure of GAG degradation causes an accumulation of partially degraded GAG inside lysosomes, which leads to an elevation of GAG fragments in urine, blood, and cerebral spinal fluid and cell, tissue, and organ dysfunction. Replacement of the deficient enzyme with an exogenous enzyme is one option to treat individuals with MPS.

MPS I can be classified into three subtypes: Hurler (severe), Hurler-Scheie, or Scheie (mild) syndrome. Some common symptoms are joint stiffness, corneal clouding, and ear, nose, and throat infections. MPS I is an autosomal recessive disorder caused by a deficiency of alpha-L-iduronidase. This leads to an accumulation of dermatan sulfate and heparan sulfate. Laronidase (Aldurazyme), a polymorphic variant of the human enzyme alpha-L-iduronidase, was approved by the US Food and Drug Administration (FDA) as an orphan drug (a drug used to treat, prevent, or diagnose a rare disease), for individuals with Hurler and Hurler-Scheie forms of MPS I and for those with the Scheie form who have moderate-to-severe symptoms. The risk and benefits of treating mildly affected patients with the Scheie form have not been established.

MPS II, also known as Hunter syndrome, is an X-linked disorder caused by a deficiency of iduronate-2-sulfatase leading to the accumulation of heparan sulfate and dermatan sulfate. Some common symptoms are skeletal abnormalities, hepatosplenomegaly, and mental retardation. Early onset (1 to 2 years) is associated with the severe form of MPS II. Idursulfase (Elaprase) was approved by the FDA as an orphan drug for individuals with MPS II or Hunter syndrome. Idursulfase (Elaprase) is a purified form of human iduronate-2-sulfatase.

MPS III, also known as Sanfilippo syndrome, has subtypes A to D. Some common symptoms are progressive intellectual disability and loss of previously acquired skills. This type leads to an accumulation of heparan sulfate. It is primarily a brain disease making enzyme replacement therapy not an option for treatment because the exogenous enzyme is unable to cross the blood-brain barrier.

MPS IV, also known as Morquio syndrome, is a progressive disease with predominant skeletal manifestations, such as skeletal abnormalities, loose joints, and underdevelopment of odontoid process. MPS IV has two forms: A and B. MPS IV A is caused by galactosamine-6-sulfatase deficiency causing a buildup of keratan sulfate and chondroitin sulfate. MPS IVB is caused by beta-galactosidase deficiency causing a buildup of keratan sulfate. Of MPS IV, only MPS IV A can be treated with exogenous enzymes. The FDA-approved elosulfase alfa (Vimizim®), a purified human enzyme N-acetyl-galactosamine-6-sulfatase, is an orphan drug for MPS IVA.

MPS V is now known as Scheie syndrome, a subtype of MPS I.

MPS VI, also known as Maroteaux-Lamy syndrome, is an autosomal recessive disorder caused by a mutation in arylsulfatase B leading to an accumulation of dermatan sulfate and chondroitin 4-sulfate. Galsulfase (Naglazyme), purified human enzyme galsulfase, was approved by the FDA in May 2005 to improve walking and stair-climbing capacity in individuals with MPS VI.

MPS VII, also known as Sly syndrome, is an autosomal recessive disorder caused by a mutation in beta-glucuronidase leading to an accumulation of heparan sulfate, dermatan sulfate, chondroitin-4-sulfate, and chondroitin-6-sulfate. Vestronidase alfa-vjbk (Mepsevii) is a recombinant human lysosomal beta glucuronidase that was approved by the FDA for the treatment of MPS VII or Sly syndrome. The effect of vestronidase alfa-vjbk (Mepsevii) has not been determined in central nervous system manifestations of MPS VII.

MPS VIII is no longer recognized.

MPS IX is a rare disorder resulting from a deficiency of hyaluronidase leading to an accumulation of hyaluronan. Currently there is no FDA-approved enzyme-replacement therapy for hyaluronidase deficiency.

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

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